The rise and deceleration of neuronal excitability in aging and Alzheimer's disease: Mechanisms, implications, and therapeutic targets.

Neuronal hyperexcitability-defined as increased likelihood of action potential firing in response to stimuli-has emerged as a key pathophysiological feature in both normal aging and Alzheimer's disease (AD). This review synthesizes current evidence across species and models, evaluating the prevalence, mechanisms, and consequences of heightened excitability at the cellular and network levels. We examine electrophysiological and imaging-based indicators of hyperexcitability, including enhanced spontaneous firing, increased calcium transients, and subclinical epileptiform activity. Data from rodent models and human studies reveal that hyperexcitability arises early in aging and AD, affecting key regions such as the hippocampus, prefrontal cortex, locus coeruleus, and spinal motor circuits. Importantly, this phenomenon is not uniformly pathological: some aged individuals, including so-called "super-agers," retain stable excitability profiles, suggesting the existence of protective mechanisms. We further explore the functional impact of hyperexcitability, including impaired cognitive encoding, gait disturbances, muscle fatigue, and neuromuscular junction degradation. In the later stages of the disease, neuronal activity tends to shift toward hypoexcitability or shows a deceleration of prior hyperexcitability, primarily driven by progressive synaptic loss, accumulation of tau pathology, and metabolic failure. Current gaps in knowledge include the lack of longitudinal data, limited translation from animal models, and insufficient understanding of compensatory vs. detrimental excitability shifts. Emerging strategies-ranging from pharmacological modulation to neuromodulation and metabolic interventions-offer potential therapeutic avenues. We propose future directions including computational modeling, humanized chimeric models, and excitability biomarkers to guide intervention. Overall, neuronal hyperexcitability represents both a biomarker and modifiable contributor to aging- and AD-related decline. Its study offers a window into early-stage dysfunction and a target for disease-modifying interventions. This review critically examines the emerging evidence for neuronal hyperexcitability as a defining feature of brain aging and AD. We begin by clarifying the concept of hyperexcitability and outlining key cellular and network-level indicators used to detect it. We then synthesize findings on hyperexcitability in aging individuals, both human and animal, and extend this analysis to AD, highlighting overlapping and divergent mechanisms. A focused section explores how motor neuron hyperexcitability contributes to functional decline, followed by a discussion of the transition from early hyperexcitability to late deceleration of neuronal excitability across disease progression. Comparative insights across species and models are provided to underscore translational relevance. We also address current limitations and propose novel investigative directions, including circuit-level imaging and computational modeling. The review concludes with an evaluation of therapeutic strategies aimed at modulating excitability, followed by a summary of key findings and future research priorities.